Pharmacokinetic profile of defibrotide in patients with renal impairment
Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable, potentially life-threatening complication of hematopoietic stem cell transplant conditioning. Severe VOD/SOS, generally associated with multiorgan dysfunction (pulmonary or renal dysfunction),...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Dove Medical Press
2016
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4993270/ https://www.ncbi.nlm.nih.gov/pubmed/27574402 http://dx.doi.org/10.2147/DDDT.S112181 |
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author | Tocchetti, Paola Tudone, Elena Marier, Jean-Francois Marbury, Thomas C Zomorodi, Katie Eller, Mark |
author_facet | Tocchetti, Paola Tudone, Elena Marier, Jean-Francois Marbury, Thomas C Zomorodi, Katie Eller, Mark |
author_sort | Tocchetti, Paola |
collection | PubMed |
description | Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable, potentially life-threatening complication of hematopoietic stem cell transplant conditioning. Severe VOD/SOS, generally associated with multiorgan dysfunction (pulmonary or renal dysfunction), may be associated with >80% mortality. Defibrotide, recently approved in the US, has demonstrated efficacy treating hepatic VOD/SOS with multiorgan dysfunction. Because renal impairment is prevalent in patients with VOD/SOS, this Phase I, open-label, two-part study in adults examined the effects of hemodialysis and severe or end-stage renal disease (ESRD) on defibrotide pharmacokinetics (PK). Part 1 compared defibrotide PK during single 6.25 mg/kg doses infused with and without dialysis. Part 2 assessed defibrotide plasma PK after multiple 6.25 mg/kg doses in nondialysis-dependent subjects with severe/ESRD versus healthy matching subjects. Among six subjects enrolled in Part 1, percent ratios of least-squares mean and 90% confidence intervals (CIs) on dialysis and nondialysis days were 109.71 (CI: 97.23, 123.78) for maximum observed plasma concentration (C(max)); 108.39 (CI: 97.85, 120.07) for area under the concentration–time curve to the time of the last quantifiable plasma concentration (AUC(0–t)); and 109.98 (CI: 99.39, 121.70) for AUC extrapolated to infinity (AUC(0–∞)). These ranges were within 80%–125%, indicating no significant effect of dialysis on defibrotide exposure/clearance. In Part 2, defibrotide exposure parameters in six subjects with severe/ESRD after multiple doses (AUC(0–t), 113 µg·h/mL; AUC over dosing interval, 113 µg·h/mL; C(max), 53.8 µg/mL) were within 5%–8% of parameters after the first dose (AUC(0–t), 117 µg·h/mL; AUC(0–∞), 118 µg·h/mL; C(max), 54.9 µg/mL), indicating no accumulation. Defibrotide peak and extent of exposures in those with severe/ESRD were ~35%–37% and 50%–60% higher, respectively, versus controls, following single and multiple doses. One adverse event (vomiting, possibly drug-related) was reported. These findings support defibrotide prescribing guidance stating no dose adjustment is necessary for hemodialysis or severe/ESRD. |
format | Online Article Text |
id | pubmed-4993270 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Dove Medical Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-49932702016-08-29 Pharmacokinetic profile of defibrotide in patients with renal impairment Tocchetti, Paola Tudone, Elena Marier, Jean-Francois Marbury, Thomas C Zomorodi, Katie Eller, Mark Drug Des Devel Ther Clinical Trial Report Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable, potentially life-threatening complication of hematopoietic stem cell transplant conditioning. Severe VOD/SOS, generally associated with multiorgan dysfunction (pulmonary or renal dysfunction), may be associated with >80% mortality. Defibrotide, recently approved in the US, has demonstrated efficacy treating hepatic VOD/SOS with multiorgan dysfunction. Because renal impairment is prevalent in patients with VOD/SOS, this Phase I, open-label, two-part study in adults examined the effects of hemodialysis and severe or end-stage renal disease (ESRD) on defibrotide pharmacokinetics (PK). Part 1 compared defibrotide PK during single 6.25 mg/kg doses infused with and without dialysis. Part 2 assessed defibrotide plasma PK after multiple 6.25 mg/kg doses in nondialysis-dependent subjects with severe/ESRD versus healthy matching subjects. Among six subjects enrolled in Part 1, percent ratios of least-squares mean and 90% confidence intervals (CIs) on dialysis and nondialysis days were 109.71 (CI: 97.23, 123.78) for maximum observed plasma concentration (C(max)); 108.39 (CI: 97.85, 120.07) for area under the concentration–time curve to the time of the last quantifiable plasma concentration (AUC(0–t)); and 109.98 (CI: 99.39, 121.70) for AUC extrapolated to infinity (AUC(0–∞)). These ranges were within 80%–125%, indicating no significant effect of dialysis on defibrotide exposure/clearance. In Part 2, defibrotide exposure parameters in six subjects with severe/ESRD after multiple doses (AUC(0–t), 113 µg·h/mL; AUC over dosing interval, 113 µg·h/mL; C(max), 53.8 µg/mL) were within 5%–8% of parameters after the first dose (AUC(0–t), 117 µg·h/mL; AUC(0–∞), 118 µg·h/mL; C(max), 54.9 µg/mL), indicating no accumulation. Defibrotide peak and extent of exposures in those with severe/ESRD were ~35%–37% and 50%–60% higher, respectively, versus controls, following single and multiple doses. One adverse event (vomiting, possibly drug-related) was reported. These findings support defibrotide prescribing guidance stating no dose adjustment is necessary for hemodialysis or severe/ESRD. Dove Medical Press 2016-08-16 /pmc/articles/PMC4993270/ /pubmed/27574402 http://dx.doi.org/10.2147/DDDT.S112181 Text en © 2016 Tocchetti et al. This work is published and licensed by Dove Medical Press Limited The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. |
spellingShingle | Clinical Trial Report Tocchetti, Paola Tudone, Elena Marier, Jean-Francois Marbury, Thomas C Zomorodi, Katie Eller, Mark Pharmacokinetic profile of defibrotide in patients with renal impairment |
title | Pharmacokinetic profile of defibrotide in patients with renal impairment |
title_full | Pharmacokinetic profile of defibrotide in patients with renal impairment |
title_fullStr | Pharmacokinetic profile of defibrotide in patients with renal impairment |
title_full_unstemmed | Pharmacokinetic profile of defibrotide in patients with renal impairment |
title_short | Pharmacokinetic profile of defibrotide in patients with renal impairment |
title_sort | pharmacokinetic profile of defibrotide in patients with renal impairment |
topic | Clinical Trial Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4993270/ https://www.ncbi.nlm.nih.gov/pubmed/27574402 http://dx.doi.org/10.2147/DDDT.S112181 |
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